Pesticides, Agent Orange and Parkinson's · PDF filePesticides, Agent Orange and Parkinson's...
Transcript of Pesticides, Agent Orange and Parkinson's · PDF filePesticides, Agent Orange and Parkinson's...
Pesticides, Agent Orange and
Parkinson's Disease
Jeff Bronstein MD,PhD
Director SW PADRECC and UCLA
Movement Disorders
Epidemiology Studies
Study disease clusters
Small population
Case-control and Population-based
studies
Larger population
Prospective studies
Huge population
The MPTP Story
1976: Barry Kidston in Maryland acute
Parkinsonism trying to make MPPP (an
analogue of Demerol).
1982: 4 patients in Santa Clara with
acute Parkinsonism. MPTP discovered
to be the cause.
How MPTP causes Parkinsonism
MPTP MPP+ MPP+
MAO-B DAT
Farming, Pesticides, and PD
Most studies have found positive
associations.
Farming: OR 1.4 (95% CI = 1.1-1.9)
Well water: OR 1.3 (95% CI = 0.9-1.6)
Professional pesticide use: OR 1.9 (95% CI =
1.5-2.5)
Elbaz and Tranchant. 2007
Pesticide Use and PD
Brown et al. 2006
Pesticides and PD
Associations found in 4 continents (North America, Europe, Asia, Australia).
Appears to be independent of farming
BUT
Methodological concerns
Recall bias
Control population
Problems identifying individual agents
Honolulu-Asia Aging Study
Prospective cohort of 8006 Japanese-
American men born 1900-1919
Years on plantation assessed in 1965
Self report on pesticide exposure
(occupation and home exposure) assessed
in 1971
116 incident cases
Addressing Recall Bias:Prospective Cohort Study
Age-adjusted Incidence of PD* by Years of
Plantation Work (follow-up = 30 yrs)
5.8 5.4
9.210.3
0
2
4
6
8
10
12
*Rate per 10,000 person-years
Test for Trend - p=0.011
0 1-10 11-20 >20
Years of Plantation Work
Age-adjusted Incidence of PD* by Years of
Pesticide Exposure (follow-up = 24 yrs)
7.86.5
8.2
12.7
0
2
4
6
8
10
12
14
*Rate per 10,000 person-years
Test for Trend - p=0.100
0 >0-1 >1-3 >3
Cumulative Years of Pesticide Exposure
Cancer Prevention Study II
Nutrition Cohort
143,325 individuals
Enrolled in 1992
Follow up 1997, 1999, 2001
Exposure was assessed by a questionnaire (yes or no, length of exposure?)
Case identification by questionnaire, medical records then reviewed.
Ascherio et al. 2006
Cancer Prevention Study II
Nutrition Cohort
Ascherio et al. 2006
Prospective Cohort Studies
Strengths Large study population
Controlled for many possible confounds (e.g. smoking, NSAIDs)
Prospective (no recall bias)
Weaknesses Little info on duration, intensity and type of exposures
No info on specific pesticides
Potential misdiagnosis of cases
Ascherio et al. 2006
Agricultural Health Study
Kamel et al. 2007
• Prospective cohort study examining
relationship between pesticide use and human
disease
• 52,000 pesticide applicators and 32,000 spouses
from Iowa and N. Carolina enrolled 1993-97
• Detailed pesticide use information
• PD participants almost twice as likely to be exposed
to 2,4,5-T and to trifualin than non-PD (control)
participants
Strengths
Incident cases were prospective
Identified specific pesticides
Controlled for other confounds
Weaknesses
Small number of cases (self reported), limited power
Exposures self reported (agents, durations etc)
Diagnosis self reported
Agricultural Health Study
Kamel et al. 2007
Parkinson’s (PEG) Study (Beate
Ritz MD,Ph.D.)
Goal: Identify all newly diagnosed cases of PD over a 4-year period (2001-2005)
400 cases400 population controls and 200-300 (unaffected) sibling controls
Establish a lifetime history of exposure to pesticides recollections of residential historyhistorical exposure records for pesticide use (PUR)
Collect biological samplesDNA for genotypingOrganochlorine serum analysesLymphocytes for GEP and oxidative stress markers
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Determining Pesticides Exposure
DAT Polymorphisms, Maneb
and Paraquat Exposure
Table 4. Associations with PD by number of risk alleles* in the 5Õ and 3Õ region of DAT and
residential paraquat and maneb exposure in the California Central Valley study
Zero/Low High
Risk Alleles
Cases
(n= 286)
Controls
(n= 319)
ORa
95% CI
Cases
(n= 38)
Controls
(n= 15)
ORa
95% CI
0 65 80 ref 4 5 0.88 (0.22, 3.48)
1 99 117 0.98 (0.63, 1.52) 10 4 2.99 (0.88, 10.21)
2+ 122 122 1.30 (0.85, 2.00) 24 6 4.53 (1.70, 12.09)
a Odds Ratio (OR) adjusted for age (continuous), race, years of schooling, smoking (ever/never)
Ritz et al, 2009
How can we prove that a toxin
contributes to the pathogenesis of PD?
A plausible mechanism of action.
Association between a toxin and PD in
epidemiological studies.
Recapitulation of behavioral and pathological
features in cellular and animal models.
Mitochondrial Dysfunction and PD
MPTP is a complex I inhibitor
Decreased complex I and II in brains and
peripheral platelets in PD
Mitochondrial-associated genes and PD
(PINK1, DJ1, POLG, cybrids)
Rotenone Exposure and PD
Residential use more common than
commercial use.
A few case-control studies support
increase incidence but not conclusive.
Dhillon et al 2008: OR 10.9 (2.5-48)
Agriculture Health Study: OR 1.7 (few cases)
Anecdotal reports
Mechanisms of Rotenone
Toxicity
Complex I inhibition leads to oxidative
stress and energy failure at low
concentrations
Proteasome inhibition
Microtubule inhibition
Progression of Parkinson's Disease
Pathology Is Reproduced by Intragastric
Administration of Rotenone in Mice
Francisco Pan-Montojo et al. PLOS One 2010
Qu i c k T i m e ™ a n d aT IF F (Un c o m p re s s e d ) d e c o m p re s s o r
a re n e e d e d to s e e t h i s p i c t u re .
Proteasome Dysfunction and PD
Proteasome-associated genes and PD (Parkin,
UCH L1)
Decreased activity in brains and blood in PD
Alpha-synuclein is at least partially degraded by
the proteasome.
Pesticides that Lead to UPS
Inhibition
RotenoneComplex I inhibitor
Ziram and other dithiocarbamatesFungicide
Multivalent interactions
BenomylFungicide (Benzimidazole)
Binds to tubulin
Dieldrin and Endosulfan
Organochlorines (epoxicide)
Inhibits GABA-gated chloride channels
Wang et al, 2006
Ziram and Related Compounds
Dimethyl- and diethyldithiocarbamates
Widely used fungicides on fruits and nuts.
Approximately 15 million lbs were used in
the US in 2002.
C
S
S
NZn++C
S
S
N
Ziram Exposure and PD
(PEG Study)
Table 3. Ambient Occupational and Residential Maneb, Ziram, and Paraquat Exposure by Time Window of Exposure and Age of C entral Va lley of California Study Popu lation
Occupational** Residential ***
Case Control OR* 95% CI Case Control OR* 95% CI
Ziram and paraquat exposure
1974-1999 Time Window 60 years old or younger No e xposure to ziram or paraquat 28 53 1.00 ref 21 38 1.00 ref Z iram or paraquat exp only 30 29 1.90 (0.92,3.94) 35 37 1.66 (0.80,3.47) Z iram and paraquat exp 19 5 5.97 (1.94,18.33) 21 12 2.76 (1.09,7.00) Over 60 years old No e xposure to ziram or paraquat 137 141 1.00 ref 103 99 1.00 ref Z iram or paraquat exp only 84 76 1.17 (0.78,1.76) 113 112 0.88 (0.59,1.31) Z iram and paraquat exp 64 37 1.93 (1.18,3.15) 69 43 1.41 (0.86,2.29)
Wang A, Costello S, Cockburn M, Zhang X,Bronstein ,Ritz B
(submitted)
Systemic Administration of Ziram
Chou et al, 2009
Other Pesticides and PD
Paraquat Associated with increased risk of PD (in combination
with maneb and ziram)
Mechanism: Redox-cycling?
Animal model; DA cell loss and behavior
Benomyl Associated with increased risk of PD (PEG and Ag
Health)
Mechanisms: UPS-I, ALDH-I, and MT-I
Primary culture DA loss but no animal models
What about Agent Orange ?
The New York TimesOctober 12, 2009
“…the Department of Veterans
Affairs plans to add Parkinson’s
disease, ischemic heart disease
and hairy-cell leukemia to the
growing list of illnesses presumed
to have been caused by Agent
Orange, the toxic defoliant used
widely in Vietnam.”
Agent Orange
Code name for a defoliant herbicide used during the Vietnam War.
Name derived from orange drums it is shipped in
Mixture of 2 herbicides:
2,4-dichlorophenoxyacetic acid (2,4-D)
2,4,5-trichlorophenoxyacetic acid (2,4,5-T).
Contaminant: 2,3,7,8-TCDD (dioxin)
Herbicide use during Vietnam War
19 million gallons of herbicides
(11.2 of Agent orange) sprayed
over 3.6 million acres in Vietnam
1962 – 71.
86% from large scale spraying
operations (operation Ranch
Hand) – good documentation
Rest from trucks and back packs
– poor documentation
Source: Science 2007; 315:176-79
Agricultural Health Study
Agent Orange
Neurotoxicity
2,4-D: mechanism of injury is unknown and evidence for
effects on dopaminergic system is inconsistent
Inhibits microtubule assembly in cerebellar granule cell culture
Mild, transient locomotor effect in acutely exposed rats
Striatal dopamine depletion in rats administered intracerebral
injection, but no toxicity noted in mice administered sub q
injection.
TCDD: mechanism of injury is unknown but linked to oxidative
stress
Conclusions: Do pesticides contribute
to the pathogenesis of PD?
Plausible mechanisms of action. YES
Association between a toxin and PD in
epidemiological studies. YES
Recapitulation of behavioral and pathological
features in cellular and animal models. YES
Thank You
Question & Answers